How to order a genetic lab test for a patient suspected of having hereditary hemochromatosis?

How to Order Genetic Testing for Hereditary Hemochromatosis

Order HFE gene mutation analysis (testing for C282Y and H63D mutations) only after confirming elevated iron studies—specifically transferrin saturation ≥45% and/or serum ferritin >200 µg/L in women or >300 µg/L in men—as this sequential approach is more cost-effective than universal genetic screening. 1, 2

Step 1: Initial Laboratory Testing (Do This First)

Before ordering any genetic test, you must obtain:

• Serum ferritin and transferrin saturation simultaneously as your initial screening tests 3, 1, 4
• Transferrin saturation ≥45% is the diagnostic threshold with highest sensitivity for detecting hemochromatosis 1, 4
• Ferritin cutoffs: >200 µg/L in women or >300 µg/L in men indicate elevation 3, 1, 4
• Confirm elevated transferrin saturation with a second fasting specimen before proceeding 4

Critical pitfall: Ferritin can be falsely elevated by inflammation, liver disease, alcohol use, malignancy, or metabolic syndrome—exclude these causes before proceeding to genetic testing 2

Step 2: When to Order Genetic Testing

Proceed with HFE gene mutation analysis (C282Y and H63D) if: 1, 2, 4

• Transferrin saturation >45% and/or ferritin is elevated above sex-specific thresholds 1, 2
• Patient has suggestive clinical manifestations (diabetes, cardiac arrhythmias, cardiomyopathy, liver disease, hepatomegaly, cirrhosis, elevated liver enzymes, hepatocellular carcinoma, arthritis, hypogonadism, or skin pigmentation changes) 3, 1
• Patient is a first-degree relative of someone with confirmed hemochromatosis 3, 1, 5

Step 3: Pre-Test Genetic Counseling (Required)

Before ordering the genetic test, discuss with the patient: 3, 1

• Available treatment (phlebotomy) and its efficacy 3, 1
• Costs involved 3
• Impact of disease labeling on insurability and psychological well-being 3, 1
• Possibility of yet-unknown genotypes associated with hemochromatosis 3
• The fact that most C282Y homozygotes (90%) do not develop clinically significant organ damage 1

Step 4: How to Order the Test

• Order: HFE gene mutation analysis for C282Y and H63D mutations 3, 2, 4, 6
• The C282Y mutation is present in approximately 90% of patients with hereditary hemochromatosis 3, 2
• Between 60-93% of patients with hemochromatosis are homozygous for C282Y 6
• Testing for H63D is also necessary as compound heterozygosity (C282Y/H63D) can cause iron overload 3, 2

For non-European patients: Consider direct sequencing of HFE and non-HFE genes if clinical suspicion is high with elevated iron studies 4

Step 5: Interpreting Results

• C282Y homozygous (C282Y/C282Y): Confirms HFE-related hemochromatosis 2
• Compound heterozygous (C282Y/H63D): May cause iron overload but with lower penetrance; investigate other contributing causes 2
• H63D homozygous with iron overload: Further investigation for other causes needed 2
• No HFE mutations found: Consider non-HFE hemochromatosis; may need MRI to quantify hepatic iron or liver biopsy 1, 4, 7

Step 6: Additional Testing After Genetic Confirmation

If hemochromatosis is confirmed genetically: 1, 4

• Liver function tests (ALT, AST) and complete blood count 4
• Consider liver biopsy if ferritin >1,000 µg/L with elevated liver enzymes, hepatomegaly, or age >40 years to assess for cirrhosis 1, 2, 4
• ECG and echocardiography in patients with severe iron overload 1, 4
• Cardiac MRI if signs of cardiac disease or juvenile hemochromatosis 1, 4
• Screen all adult first-degree relatives with HFE genetic testing after appropriate counseling 1, 2, 4, 5

Important Caveats

• Do not screen the general asymptomatic population—there is insufficient evidence to support universal screening 3, 1
• Elevated ferritin with normal transferrin saturation is an unusual pattern for classic HFE hemochromatosis, but genetic testing is still indicated as some non-classic forms present this way 1, 2
• Only 10% of C282Y homozygotes develop clinically significant organ damage, and 50% never demonstrate elevated transferrin saturation 1
• Hepcidin measurement is not recommended for diagnosing hemochromatosis 4